Down Syndrome (DS), or trisomy 21, is the most common genetic developmental disorder that leads to mental retardation. Mouse models have implicated reduced neurogenesis and faulty synaptic development as important contributors to the mental impairment characteristic of DS. While mouse models are crucial, they cannot explain all the complexities of human brain development making it important to examine the effects of trisomy 21 in the context of human cells. Human neural development in DS has not been well studied. An innovative way to study the development of particular cell types is through the use of human pluripotent stem cells. This exploratory proposal aims to take advantage of recent reports of induced pluripotent stem cells (iPS cells) to create Down syndrome-specific pluripotent stem cells to facilitate analysis of human neural development. The first aim of this proposal is to induce pluripotent stem cells from human fibroblasts that carry the trisomy 21. The second aim will exploit this new resource by testing the feasibility of differentiating these trisomy 21 iPS cells into functional forebrain neurons. The establishment of this human trisomy 21 neuronal culture paradigm will enable studies dissecting the molecular mechanisms of at least three important research priorities in Down syndrome: neurogenesis, synapse development and function, and neurodegeneration. PUBLIC HEALTH RELEVANCE: As the most common genetic cause of mental retardation, Down syndrome is a public health concern. The proposed research will create a new model of Down syndrome to advance the study of Down syndrome neuropathophysiology. The aims of this proposal include making Down syndrome-specific human pluripotent stem cells from non-embryonic sources.